Salvador-Bahia, Brazil - April 2022
Dear Dr. Laganà,
Editor Plos One
We thank you and the reviewers again for your thoughtful suggestions that helped improve
our manuscript. We believe that this revised manuscript is a better and more balanced
representation of our research, and we hope that it is now suitable for publication
in your journal. The answers to the questions can be found below (PONE-D-21-31051).
Sincerely,
Dr. Fred Luciano Neves Santos
corresponding author
fred.santos@fiocruz.br
Author's Reply to the Review Report (Reviewer 1)
The article presents a relevant topic using novel data with sub-national and temporal
detail, potentially advancing the current understanding of CI and SiP’s geographical
diffusion and temporal evolution. I have read it with great interest and enjoyed the
manuscript in general. However, there is room for improvement in various parts, in
particular: the literature review should be extended, the data section needs to be
more detailed, the methods should include spatial econometric techniques, and the
results and discussion sections should better elaborate on the implications of the
study results and their impact on current research. (see document attached for further
details)
Question 1. The references need to be formatted properly (a lot of the journal names
are shortened),
and often the article or volume number is missing. E.g. reference number 35 should
be: Domingues RM, Szwarcwald CL, Souza PR, Leal MD. Prevalence of syphilis in pregnancy
and prenatal syphilis testing in Brazil: birth in Brazil study. Revista de saúde pública.
2014;48(5): 766-74. In one occasion you cite WHO and others World Health Organization,
it should be consistent throughout the references. Reference number 10 has the authors’
names listed in capital letters.
Reply: We thank the reviewer for bringing the standardization of references to our
attention. We have formatted the references according to the instructions at https://www.frontiersin.org/about/author-guidelines using the Harvard Reference Style (author-date).
Question 2. The literature is missing a few important publications, their careful
reading and inclusion will definitely improve the manuscript. See for instance, but
not exclusively Marques dos Santos, M., Lopes, A. K. B., Roncalli, A. G., & Lima,
K. C. D. (2020). Trends of syphilis in Brazil: a growth portrait of the treponemic
epidemic. Plos one, 15(4), e0231029. Rgjh; Soares, K. K. S., Prado, T. N. D., Zandonade,
E., Moreira-Silva, S. F., & Miranda, A. E. (2020). Spatial analysis of syphilis in
pregnancy and congenital syphilis in the state of Espírito Santo, Brazil, 2011-2018.
Epidemiologia e Serviços de Saúde, 29.
Reply: Thanks for suggesting new references. More recent studies were included in
the text.
Before: “Overall, our results indicate the existence of a distinct trend for each
form of syphilis, with an increasing tendency in case numbers over time [...] The
high number of cases of CS and SiP observed from 2011 to 2017 could have also been
due to the implementation of a governmental program in 2011 called "Rede Cegonha"
(stork program), which expanded early detection efforts as a result of periodic screening
for prenatal, intrapartum and postpartum syphilis [16].”
After (line 315-318): Overall, our results indicate the existence of an increasing
in case numbers over time. that there was an upward trend in the number of cases de
CS e SiP (2011 to 2017), which corroborates the results presented here [20,21].
Reference # 20 (line 503-505): Dos Santos MM, Lopes AKB, Roncalli AG, De Lima KC.
Trends of syphilis in Brazil: A growth portrait of the treponemic epidemic. PLoS One.
2020;15: 1–11. doi:10.1371/journal.pone.0231029.
Reference # 21 (line 506-509): Lino CM, da Luz Rosário de Sousa M, Batista MJ. Epidemiological
profile, spatial distribution, and syphilis time series: A cross-sectional study in
a Brazilian municipality. J Infect Dev Ctries. 2021;15: 1462–1470. doi:10.3855/jidc.13780.
Before: “It is important to note that changes in the epidemiologic infection profile
in recent years are likely associated with a) increased testing coverage enabled by
the adoption of rapid diagnostic tests, which therefore allowed for the expanded identification
of incident cases throughout the country […] [19]’’.
After (line 336-339): “It is important to note that changes in the epidemiologic infection
profile in recent years are likely associated with a) increased testing coverage enabled
by the adoption of rapid diagnostic tests, which therefore allowed for the expanded
identification of incident cases throughout the country [24–26] […]”
Reference # 24 (line 516-519): Roncalli AG, Rosendo TMS de S, Santos MM Dos, Lopes
AKB, Lima KC de. Effect of the coverage of rapid tests for syphilis in primary care
on the syphilis in pregnancy in Brazil. Rev Saude Publica. 2021;55: 94. doi:10.11606/s1518-8787.2021055003264.
Reference # 26 (line 524-527): De Figueiredo DCMM, De Figueiredo AM, De Souza TKB,
Tavares G, De Toledo Vianna RP. Relationship between the supply of syphilis diagnosis
and treatment in primary care and incidence of gestational and congenital syphilis.
Cad Saude Publica. 2020;36: e00074519. doi:10.1590/0102-311X00074519.
Before: “An established diagnosis does not guarantee adhesion to appropriate treatment
by the patient. The late onset of symptoms (mostly detected in the third trimester),
the interruption of and/or low attendance in prenatal examinations, difficulties in
diagnosis, a lack of information regarding infection and unsafe sexual practices have
been reported as risk factors for the development of syphilis [34–36]. Furthermore,
errors in antibiotic dosage have also been of concern. Other key factors, such as
conjugal infidelity, the absence of partners at prenatal appointments and reluctance
in adhering to treatment protocols have also been reported by patients [26,33].”.
After (line 380-383): “Nonetheless, difficulties in diagnosis, interruption of and/or
low attendance in prenatal examinations, non-adherence or inadequate treatment regarding
antibiotic dosage, and absence of partners at prenatal appointments have been reported
as risk factors for the development and non-interruption of syphilis [42–47].”
Reference # 47 (line 596-599): Amorim EKR, Matozinhos FP, Araújo LA, Silva TPR da.
Tendência dos casos de sífilis gestacional e congênita em Minas Gerais, 2009-2019:
um estudo ecológico. Epidemiol e Serv saude Rev do Sist Unico Saude do Bras. 2021;30:
e2021128. doi:10.1590/S1679-49742021000400006.
Before: “In fact, STI and SiP were found to be more strongly associated with women
who dropped out of school, self-identified as 'black' or 'mixed-race', were under
20 years of age or between 20 and 30 years old [41], had limited access to quality
health services, preventive and educational programs or received assistance at public
health care units, but without adequate prenatal care [25,35,36].”
After (line 390-394): “[…] that identified a significant correlation between SiP and
women who dropped out of school, self-identified as 'black' or 'mixed-race', age below
20 years or between 20 and 30 years old [48], without access to quality health services,
preventive and educational programs or received assistance at public health care units,
including adequate prenatal care [34,44,45,54,55].”
Reference # 54 (line 624-626): Bezerra MLDMB, Fernandes FECV, Nunes JPDO, Baltar SLSMDA,
Randau KP. Congenital syphilis as a measure of maternal and child healthcare, brazil.
Emerg Infect Dis. 2019;25: 1469–1476. doi:10.3201/eid2508.180298.
Before: “The present study identified spatial clusters of municipalities with high
rates of CS and SiP in Brazil. Between 2001 and 2017, almost all microregions of the
country reported a higher intensity of CS and SiP infections.”
After (line 409-411): “The present study identified spatial clusters of municipalities
with high rates of CS and SiP in Brazil. Between 2001 and 2017, almost all regions
and microregions of the country reported a higher intensity of CS and SiP infections
[47,54,57–62].”
Reference # 47 (line 596-599): Amorim EKR, Matozinhos FP, Araújo LA, Silva TPR da.
Tendência dos casos de sífilis gestacional e congênita em Minas Gerais, 2009-2019:
um estudo ecológico. Epidemiol e Serv saude Rev do Sist Unico Saude do Bras. 2021;30:
e2021128. doi:10.1590/S1679-49742021000400006.
Reference # 54 (line 624-626): Bezerra MLDMB, Fernandes FECV, Nunes JPDO, Baltar SLSMDA,
Randau KP. Congenital syphilis as a measure of maternal and child healthcare, brazil.
Emerg Infect Dis. 2019;25: 1469–1476. doi:10.3201/eid2508.180298.
Reference # 57 (line 633-636): Medeiros JAR, Yamamura M, da Silva ZP, Domingues CSB,
Waldman EA, Chiaravalloti-Neto F. Spatiotemporal dynamics of syphilis in pregnant
women and congenital syphilis in the state of São Paulo, Brazil. Sci Rep. 2022;12.
doi:10.1038/s41598-021-04530-y.
Reference # 58 (line 637-641): Nunes PS, Guimarães RA, Rosado LEP, Marinho TA, Aquino
ÉC de, Turchi MD. Tendência temporal e distribuição espacial da sífilis gestacional
e congênita em Goiás, 2007-2017: um estudo ecológico. Epidemiol e Serv saude Rev
do Sist Unico Saude do Bras. 2021;30: e2019371. doi:10.1590/S1679-49742021000100002.
Reference # 59 (line 642-645): Soares MAS, Aquino R. Completude e caracterização dos
registros de sífilis gestacional e congênita na Bahia, 2007-2017. Epidemiol e Serv
saude Rev do Sist Unico Saude do Bras. 2021;30: e20201148. doi:10.1590/S1679-49742021000400018.
Reference # 60 (line 646-649): De Souza TA, Teixeira KK, Santana RL, Penha CB, Medeiros
ADA, De Lima KC, et al. Intra-urban differentials of congenital and acquired syphilis
and syphilis in pregnant women in an urban area in northeastern Brazil. Trans R Soc
Trop Med Hyg. 2021;115: 1010–1018. doi:10.1093/trstmh/trab011
Reference # 61 (line 650-654): de Mélo KC, Dos Santos AGG, Brito AB, de Aquino SHS,
Alencar ÉTDS, Duarte EM da S, et al. Syphilis among pregnant women in Northeast Brazil
from 2008 to 2015: A trend analysis according to sociodemographic and clinical characteristics.
Rev Soc Bras Med Trop. 2020;53: 1–6. doi:10.1590/0037-8682-0199-2019.
Reference # 62 (line 655-658): Soares KKS, Prado TN do, Zandonade E, Moreira-Silva
SF, Miranda AE. Spatial analysis of syphilis in pregnancy and congenital syphilis
in the state of Espírito Santo, Brazil, 2011-2018. Epidemiol e Serv saude Rev do
Sist Unico Saude do Bras. 2019;28: e2018197. doi:10.5123/S1679-49742019000300005.
Question 3. The paper does not present any reference to the spatial nature of the
data from an econometric point of view. It would be useful to add Global and Local
Moran’s I (or similar indexes) to measure the non randomness of spatial clusters,
especially using LISA plots and bivariate LISA plots. See for instance: Brooks, M.
M. (2019). The advantages of comparative LISA techniques in spatial inequality research:
Evidence from poverty change in the United States. Spatial Demography, 7(2), 167-193.;
Yin, F., Feng, Z., & Li, X. (2012). Spatial analysis of primary and secondary syphilis
incidence in China, 2004-2010. International journal of STD & AIDS, 23(12), 870-875,
Graepp Fontoura, I., Lima, V. C., Fontoura, V. M., Santos, F. S., de Jesus Costa,
A. C. P., de Oliveira, F. J. F., ... & Santos Neto, M. (2021). Spatial analysis of
congenital syphilis in a federative unit in northeastern Brazil. Transactions of The
Royal Society of Tropical Medicine and Hygiene, 115(10), 1207-1217. And more in general:
Anselin, L. (2001). Spatial econometrics. A companion to theoretical econometrics,
310330.
Reply: We thank the reviewer for his/her criticism and politely ask him/her to reconsider
this opinion. The implicit hypothesis of the calculation of the Moran index is the
stationary of the first and second order, and the index loses its validity when calculated
for nonstationary data. When there is a non-stationary of first order (trend), the
neighbors will tend to have closer values than the ones more distant because each
value is compared to the global average, inflating the index. For more details, please
read the paper below:
Naizer CCBR, Rodrigues DS, Pedreira Junior JU, Pitombo CS. G-SIVAR: a global spatial
indicator based on variogram. Bol. Ciênc. Geod. 25 (4), 2019.
https://doi.org/10.1590/s1982-21702019000400022
Question 4. In the abstract, you mention that CS and SiP is more prevalent among mixed
race individuals (newborns and women) but on p.8 the picture is different, and it
is described to vary according to macro-regions. Different regions in Brazil have
different ethnic compositions, you should make that clear earlier on.
Reply: We thank the reviewer for this comment. The following sentence has been revised
for clarification:
Before: “The epidemiological profile of Brazil indicates most reported CS cases occurred
among ‘mixed-race’ newborns who were diagnosed within seven days after birth and whose
mothers had received prenatal care.”
After (line 37-40): In general, the epidemiologic profile of Brazil indicates most
reported CS cases occurred in "mixed-race" newborns who were diagnosed within seven
days of birth and whose mothers had received prenatal care, but the epidemiologic
profile varies by Brazilian macroregion.
Question 5. Moreover, in the legend in Figures 3 and 4, you report the classifications
as translated from Portuguese, which sounds off in English. The authors might want
to revise and update that. I suppose 'Brancos' would be individuals of European descent,
'Amarelos' would be of East Asian descent, etc.
Reply: We have revised the shelf-reposted skin color throughout the manuscript and
in the legends of Figures 3 and 4. We also added a sentence at the end of the Study
Design subsection that reads as follows:
After: no text.
Before (line 147-150): Self-reported skin color was classified as European ancestry,
dark skin, East Asian ancestry, indigenous ancestry, mixed-race (persons whose skin
color is not classified as dark-skinned, European, indigenous, or East Asian).
Question 6. The Study design section would benefit from a more thorough description
of the ethnic categories used. Mixed race is for any mixed race, as in anyone who
does not identify as either of black, white, indigenous, or East Asian descent?
Reply: Yes, mixed-race refers to anyone that no shelf-reported skin color as dark
skin, European ancestry, indigenous, or East Asian ancestry. In order to clarify the
concept of “mixed-race”, we have added the following sentence in the end of the Study
Design subsection:
After: no text.
Before (line 147-150): Self-reported skin color was classified as European ancestry,
dark skin, East Asian ancestry, indigenous ancestry, mixed-race (persons whose skin
color is not classified as dark-skinned, European, indigenous, or East Asian).
Question 7. In fig 3 and 4 you present bar charts over Brazil’s macro regions map.
However, a lot of information is missed because of charts resizing to fit within each
macro-region. I would arrange the bar charts without the map, and add for each macro-region
the population composition (the main group). That way, it’d be easier to interpret
CI and SiP prevalence in said category, whether it is just representative of the population
composition or of a disadvantaged population group (I believe the South is predominantly
white so it’s not a shocker that most CI children are white). One example that comes
to mind is the share of Covid deaths among Alaskans, where 30% of Covid19-related
deaths were registered among Alaskan Natives, although they represent 15% of the total
Alaska population.
(https://coronavirus.jhu.edu/data/disparity-explorer). In figure 4: Years spent in education.
Reply: We thank the reviewer for this excellent suggestion. However, we would like
to ask the reviewer to reconsider his/her criticism. The data available in the databases
do not allow us to extract the national population (or each Brazilian region) according
to the variables studied. Therefore, we would like to continue presenting the data
as they were presented in the first version of the manuscript.
Question 8. In figure 4: Years spent in education.
Reply: We thank the reviewer for this comment. We have replaced "Years of study" with
"Years spent in education".
Question 9. In the spatiotemporal description of results the regions mentioned may
not be familiar with audiences outside of Brazil. Are those mainly rural, urban, tropical
or large cities?
Reply: The names of the states in which the microregions are located are given in
the text, e.g., SE, TO, AM, MG, etc. In addition, the 15 microregions with the most
cases are shown on the map in Figure 7 so that the reader outside Brazil knows where
they are located. We thank the reviewer for his/her criticism and politely ask him/her
to reconsider this opinion. All microregions are tropical and consist of several rural
and urban areas, with large and small cities.
Question 10. The results and discussion can be improved by contextualizing them. For
instance, you mention Cassilandia, which is a small city at the border with Mato Grosso:
elaborate on why its results are relevant when compared to other cities.
Reply: We thank the reviewer for this comment. Indeed, as mentioned, the results of
Fig. 7 are sometimes not put into proper context in the discussion. These results
show the main microregions in Brazil that, according to the Ministry of Health, had
high incidence rates during the period studied. However, for most of these microregions,
there are no published studies to support our discussion. Therefore, we discuss these
results in general, as presented in lines 415-416. We may add one additional piece
of information in this paragraph.
Before: “Between 2001 and 2017, almost all microregions of the country reported a
higher intensity of CS and SiP infections.”
After (line 410-413): “Between 2001 and 2017, almost all regions and microregions
of the country reported a higher intensity of CS and SiP infections [47,54,57–62].
However, in most of Brazil's microregions, there are few studies of these regions
that do not highlight these areas as priority for a syphilis surveillance study.”
Question 11. How does under-reporting, and its decrease in the last 15 years affect
the results and its interpretation? Are there population subgroups most likely to
be missed?
Reply: Thank you for the relevant question. We have entered the answer to this as
a paragraph of the discussion.
Before: No text.
After (line 433-440): “As a limitation, we consider that by syphilis is a reemerging
infection with epidemic behavior in Brazil, the numbers of reported cases vary widely,
indicating possible underreporting. This problem affects the results and interpretation
of epidemiological studies, since it is not possible to draw concrete conclusions
about the effectiveness of diagnosis and treatment of patients in the public health
network, and about the implementation and correct monitoring of prenatal care. Mandatory
reporting of cases helps in the evaluation of public health policies. On the other
hand, both acquired syphilis, including in pregnant women, and congenital syphilis
pose the same problem”.
Question 12. The article needs careful revision, there are typos throughout the text,
as well as some
expressions that should be improved (see below a few examples).
Reply: We thank the reviewer for this comment. The English language was revised by
Andris K. Walter, a native American speaker. The author's intent has not been distorted
in any way by the revision.
Question 13. P3. line 60: condom-less sex (unprotected intercourse?)
Reply: Yes, condom-less sex means unprotected sex. In order to avoid any misinterpretation,
we have changed the text as follows:
Before: “…is mainly transmitted through condomless sex (acquired syphilis) […]”.
After (line 66-67): ‘’…is mainly transmitted through unprotected intercourse (acquired
syphilis) […]’’.
Question 14. P.3 line 62 space before full stop.
Reply: Thank you for bringing this error to our attention. We have removed the space
before the period.
Before: “…by exposure to blood or contaminated body fluids [5–8]. In vertical …”
After (line 68): …by exposure to blood or contaminated body fluids [5–8]. In vertical
…
Question 15. P.3 line 67 parenthesis misplaced.
Reply: Thank you for bringing this error to our attention. We have removed the incorrectly
placed brackets.
Before: “Despite the existence of diagnostic tests and (effective antibiotic treatment…”
After (line 73): “Despite the existence of diagnostic tests and effective antibiotic
treatment …’’
Question 16. Page 4 ends with a title.
Reply: We have fixed this formatting error. The title has been replaced at the top
of the next page.
Question 17. Line 188: you don’t mention the male to female ratio for the general
pop.
Reply: Line 188 refers to the annual percentage change in syphilis cases. The question
about the ratio between males and females was not clear. We are available for further
clarification.
Question 18. L. 201: suggesting a lack of protection against CS: lack of prenatal
screening? Or
condom use?
Reply: We thank the reviewer for this comment. The expression "lack of protection
against CS" refers to "lack of prenatal screening". We have adjusted the sentence
accordingly.
Before: “With respect to prenatal care among the CS cases, over 70% reported receiving
prenatal care regardless of period and macroregion, suggesting a lack of protection
against CS.”
After: (line 223-225): “With respect to prenatal care among the CS cases, over 70%
reported receiving prenatal care regardless of period and macroregion, lack of prenatal
screening”.
Question 19 L. 211: you only mention here that race is self-reported, you should mention
this in the data section as well
Reply: We have revised the shelf-reposted skin color throughout the manuscript and
in the legends of Figures 3 and 4. We also added a sentence at the end of the Study
Design subsection that reads as follows:
After: no text.
Before: (line 147-150): “Self-reported skin color was classified as European ancestry,
dark skin, East Asian ancestry, indigenous ancestry, mixed-race (persons whose skin
color is not classified as dark-skinned, European, indigenous, or East Asian)’’.
Author's Reply to the Review Report (Reviewer 2)
This analysis and findings are valuable for the surveillance of maternal and congenital
syphilis Brazil. These findings are of considerable concern regarding the risk of
syphilis in women and unborn infants. There are many opportunities to shorten and
streamline the discussion and provide updated references to reflect national, regional
and global efforts to eliminate mother to child transmission of syphilis. Please find
attached my comments that exceed the character count.
Question 1. Major comment: Line 37 Abstract and in methods, results of paper. The
WHO global estimates of CS use the number of live births as the denominator for the
calculation of rate of congenital syphilis. In order to have these results considered
at the regional and global levels, use of the global case rate definition would be
of greater value. Also the WHO criteria for recognizing national elimination of mother
to child transmission of syphilis (EMTCT) is <50 cases/100,000 ‘live births’. This
analysis could contribute “directly” to Brazil’s national and provincial monitoring
and surveillance of SiP and CS towards EMTCT if the rates of CS were calculated according
to global case rate definitions.
a. https://www.who.int/publications/i/item/9789240039360
b. https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002329
c. https://www.who.int/reproductivehealth/congenital-syphilis/WHO-validation-EMTCT/en/
d. https://www.who.int/reproductivehealth/congenital-syphilis/emtc-gvac/en/
Reply: We thank the reviewer for this excellent proposal and fully agree with the
suggestion to improve the presentation of the data. The data obtained from the new
analyzes are included in the new version of the manuscript.
Question 2. Abstract line 45-46, please provide the values that increased 4000%...
from what to what?
Reply: We thank the reviewer for this comment. We found an error in this information
and made the correction suggested in the abstract (line 45-46) and in the results
(line 279-280).
Abstract section:
Before: “… and the relative risk of SiP increased around 4,000%’’.
After (line 46-47): … and the relative risk (RR) of SiP increased around 400% (RR:
1,00 to 445,50)’’
Results section:
Before: “From 2001 to 2018 the relative risk of SiP increased about 4,000% in the
country…”
After (line 285-286): From 2001 to 2018 the RR of SiP increased about 400% in the
country (RR: 1,00 to 445,50)…
Question 3. Introduction line 54, need to use the most recent WHO estimates for syphilis
a. https://pubmed.ncbi.nlm.nih.gov/31384073/
b. Rowley J, Vander Hoorn S, Korenromp E, et al. Chlamydia, gonorrhoea, trichomoniasis
and syphilis: global prevalence and incidence estimates, 2016 WHO Bulletin. 2019;
97:548-562.
Reply: Thank you for the suggestion to update the information. This data is now more
current. We have made the suggested correction by changing the reference.
Before: “Increasing incidence and prevalence has been reported since 2008 in adults
between 15 and 49 years of age, being 10.6 million cases of syphilis”.
After (line 54-57): According to the number of reported cases of curable STIs in 2016,
only 6.3 million (1.67%) were syphilis in women and men aged 15-49 years. Looking
at the period from 2012 to 2016, the estimated global prevalence was 0.5% and the
incidence was estimated at 1.7 cases per 1,000 women and 1.6 cases per 1,000 men [2].
Question 4. Introduction line 56, need to use the most recent WHO estimates for congenital
syphilis
a. https://pubmed.ncbi.nlm.nih.gov/30811406/
Korenromp EL, Rowley J, Alonso M, et al. Global burden of maternal and congenital
syphilis and associated adverse birth outcomes – estimates for 2016 and progress since
2012. PLOS One. 2019. 14(2): e0211720.
Reply: Thank you for your suggestion. We have made the suggested correction and changed
the reference.
Before: “Around one million pregnant women become infected each year, resulting in
approximately 300,000 fetal and neonatal deaths, placing more than 200,000 children
at risk of premature death.”
After (line 57-63): In 2016, the estimated global prevalence of syphilis in pregnant
women was 0.69%, resulting in a global congenital syphilis rate of 473 cases per 100,000
live births (~661,000 total cases). The data showed that maternal syphilis caused
143,000 early fetal deaths and stillbirths, 61,000 neonatal deaths, 41,000 preterm
or low birth weight births, 109,000 infants with clinical congenital syphilis, and
306,000 cases of infants without clinical signs in mothers with untreated syphilis
[3].
Question 5. Introduction: Line 63, would delete “following direct contact with bacterium
by the mother”.
Reply: We thank the reviewer for his/her comment and have deleted the sentence as
requested:
Before: “In vertical transmission from mother-to-child (CS), following direct contact
with the bacterium by the mother, infection spreads to the fetus hematologically,
predominantly via the transplacental route [9,10].”
After (line 68-70): In vertical transmission from mother-to-child (CS), the infection
spreads to the fetus hematologically, predominantly via the transplacental route [10,11].
Question 6. Lines 76-86. Please see the proposed edited language for better clarity
and consistency with other published references on maternal and congenital syphilis
terminology.
“According to the Brazil MoH, women diagnosed with syphilis during pregnancy, at delivery
and / or puerperium should be reported as SiP. This case definition includes symptomatic
or asymptomatic pregnant women with at least one reactive syphilis test, either treponemal
or nontreponemal (of any titer), and without previous recorded syphilis treatment.
The case definition of CS includes: all newborns, stillbirths or abortions from women
diagnosed with syphilis that have not been treated or who received inadequate treatment,
children under 13 years of age with clinical manifestations, radiographic or radiological
alterations and reactive nontreponemal or treponemal syphilis tests, and children,
products of abortion or stillbirth with biopsy or necropsy microbiological evidence
of T. pallidum infection in a sample of nasal discharge or skin lesion, detection
of T. pallidum by means of direct exams by microscopy (dark field or with colored
material) [13].”
Reply: We thank the reviewer for this valuable contribution. The text has been clarified
and we have changed the sentence as suggested:
Before: “According to the MoH, it is defined that all cases of women diagnosed with
syphilis during prenatal, delivery and / or puerperium should be reported as SiP.
Being symptomatic or asymptomatic, it is necessary to present at least one reagent
test, being treponemic and / or non-treponemic with any titration and without previous
treatment record. For SC, it is considered a case, every newborn, stillborn or abortion
of a woman with syphilis that is not treated or treated in an inadequate way; every
child under 13 years of age with clinical manifestations, radiographic or radiological
alterations and non-treponemic or treponemic reagent tests; microbiological evidence
of T. pallidum infection in a sample of nasal discharge or skin lesion, biopsy or
necropsy of a child, abortion or stillbirth; detection of T. pallidum by means of
direct exams by microscopy (dark field or with colored material) [13]’’.
After (line 82-93): “According to the Brazil MoH, women diagnosed with syphilis during
pregnancy, at delivery and / or puerperium should be reported as SiP. This case definition
includes symptomatic or asymptomatic pregnant women with at least one reactive syphilis
test, either treponemal or nontreponemal (of any titer), and without previous recorded
syphilis treatment. The case definition of CS includes: all newborns, stillbirths
or abortions from women diagnosed with syphilis that have not been treated or who
received inadequate treatment, children under 13 years of age with clinical manifestations,
radiographic or radiological alterations and reactive nontreponemal or treponemal
syphilis tests, and children, products of abortion or stillbirth with biopsy or necropsy
microbiological evidence of T. pallidum infection in a sample of nasal discharge or
skin lesion, detection of T. pallidum by means of direct exams by microscopy (dark
field or with colored material) [14]’’.
Question 7. Lines 88-89. Please provide appropriate references for the statements
regarding increases in syphilis. Reference 14 is from 2015 and likely reflects data
from several years prior. Consider using the WHO global estimates of syphilis (Rowley
et al. described earlier) and the US CDC 2019 surveillance report https://www.cdc.gov/std/statistics/2019/default.htm for the US as current references.
Reply: We thank the reviewer for this valuable contribution. We have only added Rowley's
reference, which provides more general and up-to-date data.
Before: “Globally, rising numbers of syphilis cases have also been reported in the
United States, Canada, Europe, Russia and China…”
After (line 94-96): “Globally, an increasing number of syphilis cases have also been
reported in Africa, the Americas, the Eastern Mediterranean, Europe, Southeast Asia,
and the Western Pacific [2,3] […]’’
Question 8. Methods: please describe in more detail the joinpoint method of identifying
the year intervals of analysis.
Reply: Thank the reviewer for his/her comment. We have inserted the following sentence
in the Statistical analysis subsection:
Before: “…Temporal changes in annual incidence rates were calculated using the joinpoint
regression model and expressed as Annual Percentage Change (APC) with 5% significance
(p < 0.05). Digital maps were obtained from…”
After (line 162-176): “Temporal changes in annual incidence rates were calculated
using the joinpoint regression model and expressed as Annual Percentage Change (APC)
with 5% significance (p < 0.05) using the NCI Joinpoint regression program version
4.1.1 [17,18]. To determine the optimal number of joinpoints, sequential permutation
tests were performed during model selection. Each of the permutation tests performs
a test of the null hypothesis H0: number of joinpoints = ka against the alternative
Ha: number of joinpoints = kb with ka < kb. The procedure starts with ka = MIN or
minimum number of joinpoints and kb = MAX or maximum number of joinpoints, in our
case 0 and 5, respectively. Monte Carlo simulation, with the number of permutations
fixed at 4,499, is used to calculate the permutation p-value for each hypothesis test.
Based on the Joinpoint Regression Program recommendations for the number of time points
of observations in our study, our analyzes allowed for a maximum of five joinpoints,
meaning that between one and six trend segments could be included in the final model,
depending on the number of joinpoints detected [19]’’.
Question 9. What does a skin color of ‘yellow’ imply? The skin colors are difficult
to interpret without the addition of information related to culture, origin, or ethnicity.
(Asian, Hispanic, Aboriginal, African etc). “Mixed-race” is used but it is unclear
how the other races can be derived from skin color alone. If alternatives or co-naming
(e.g. yellow = Asian decent) are not possible would explain the historical context
of this color-based naming.
Reply: We agree with the reviewer and have revised the shelf-reposted skin color throughout
the manuscript and in the legends of Figures 3 and 4. We have also added a sentence
at the end of the Study Design subsection that reads as follows. Indeed, yellow =
Asian ancestry; white = European ancestry.
After: no text.
Before (line 147-150): Self-reported skin color was classified as European ancestry,
dark skin, East Asian ancestry, indigenous ancestry, mixed-race (persons whose skin
color is not classified as dark-skinned, European, indigenous, or East Asian).
Question 10. Discussion: line 292. The use of “tendency” is unclear. Consider rate
of case number.
Reply: Thank you for the suggestion to change the term used.
Before: “… with an increasing tendency in case numbers over time…”
After (line 316): … an increasing in case numbers over time…
Question 11. Discussion Lines 296-299. Would consider describing Rede Cegonha later
in the discussion alongside penicillin shortages.
Reply: We agree with the change and appreciate the suggestion.
Before: “The high number of cases of CS and SiP observed from 2011 to 2017 could have
also been due to the implementation of a governmental program in 2011 called "Rede
Cegonha" (stork program), which expanded early detection efforts as a result of periodic
screening for prenatal, intrapartum and postpartum syphilis [16]”.
After (line 336-341): It is important to note that changes in the epidemiologic infection
profile in recent years are likely associated with a) increased testing coverage enabled
by the adoption of rapid diagnostic tests, which therefore allowed for the expanded
identification of incident cases throughout the country [24–26], b) the shortage of
benzathine penicillin, which, since 2014, has affected Brazil, as well as other countries,
due to a deficit of raw materials required for its production [27], and c) implementation
of a governmental program in 2011 called "Rede Cegonha" (stork program), which expanded
early detection efforts as a result of periodic screening for prenatal, intrapartum
and postpartum syphilis [28].
Question 12. Discussion line 295: instead of “syphilis remains a national public
health concern” consider that “syphilis should be “prioritized” as a national public
health concern due to the dramatic increases in rates of SiP and CS”. This would
be a good ending for the first paragraph.
Reply: We thank the reviewer for this valuable contribution.
Before: “Regardless, the increase in cases witnessed in recent years suggests that
syphilis remains a national public health concern.”
After (line 319-321): “Regardless, the increase in cases witnessed in recent years
suggests that syphilis should be “prioritized” as a national public health concern
due to the dramatic increases in rates of SiP and CS’’.
Question 13. The discussion is quite long and repeats information about gender of
babies and race of mothers. Would recommend shortening and removing redundancy.
Reply: We appreciate the suggestion. Possible changes have been made to improve readability.
Before: “Herein, most cases of CS were diagnosed less than seven days after birth,
and 70% of mothers reported receiving prenatal care. Most cases of CS are asymptomatic
at birth, however, the high coverage of hospital births with a notification system
for CS based on maternity services are the main reason why diagnosis usually occurs
within seven days after birth (typically between the 1st and 2nd day of life) [31,32].
Contrarily, in addition to prematurity, newborns can present signs and symptoms of
infection soon after birth, including low birth weight, anemia, jaundice, respiratory
distress, visceromegaly, congenital malformations, serosanguinous discharge and rhinitis,
skin lesions, heart disease and/or hearing loss [33]. Interestingly, it was found
that despite the predominance of prenatal care in 70+% of the CS cases investigated
herein, significantly high numbers of cases of CS were nonetheless reported throughout
the country […]”.
After (line 357-363): “Herein, most cases of CS were diagnosed in asymptomatic children
less than seven days after birth with 70% mothers reported receiving prenatal care.
However, the high coverage of hospital births with a notification system for CS based
on maternity services are the main reason why diagnosis usually occurs within seven
days after birth (typically between the 1st and 2nd day of life) [33,34]. Interestingly,
it was found that despite the predominance of prenatal care in 70+% of the CS cases
investigated herein, significantly high numbers of cases of CS were nonetheless reported
throughout the country”.
Before: “However, despite the expansion of diagnosis and treatment in Brazil, increases
in the number of cases indicates shortcomings in the efforts designed to control and
prevent this STI [34]. At the same time, health authorities have also attributed increases
in incidence to the success of public health actions in improving detection rates.
Nevertheless, actions designed to improve health care access for pregnant women have
performed poorly in terms of CS prevention [26]. One of the main purposes of prenatal
care is to assist women in a qualified and humanized way beginning in the early stages
of pregnancy, adopting early screening procedures coupled with timely interventions
[35]. Early diagnosis and treatment of SiP, ideally before the 20th week of pregnancy,
can reduce CS-related cases, such as miscarriages, stillbirths, and infant deaths
[36]. It is therefore important that all pregnant women be tested at the first prenatal
visit scheduled in the first trimester of pregnancy, with repeat testing performed
at around 28 weeks (beginning of the third trimester) and on admission to childbirth
in order to promptly implement appropriate therapy if necessary [37-40]. Information
regarding CS vertical transmission should be provided to pregnant women at the onset
of prenatal care, and physicians must inform patients regarding the risks and consequences
of the disease to the mother and her fetus [30,41] ….. An established diagnosis does
not guarantee adhesion to appropriate treatment by the patient. The late onset of
symptoms (mostly detected in the third trimester), the interruption of and/or low
attendance in prenatal examinations, difficulties in diagnosis, a lack of information
regarding infection and unsafe sexual practices have been reported as risk factors
for the development of syphilis [42–44]. Furthermore, errors in antibiotic dosage
have also been of concern. Other key factors, such as conjugal infidelity, the absence
of partners at prenatal appointments and reluctance in adhering to treatment protocols
have also been reported by patients [41,45]’’.
After (line 368-383): “Despite the expansion of diagnosis and treatment in Brazil,
increases in the number of cases indicates shortcomings in the efforts designed to
control and prevent this STI [36]. At the same time, health authorities have also
attributed increases in incidence to the success of public health actions in improving
detection rates. Nevertheless, actions designed to improve health care access for
pregnant women have performed poorly in terms of CS prevention [25]. Early diagnosis
and treatment of SiP can reduce CS-related cases, such as miscarriages, stillbirths,
and infant deaths [37]. Therefore, it is important that all pregnant women be tested
at the first prenatal visit scheduled (1st trimester), with 28 weeks pregnant and
at the time of delivery in order to promptly implement appropriate therapy if necessary
[32,38–42]. Information regarding CS vertical transmission should be provided to pregnant
women at the onset of prenatal care, and physicians must inform patients regarding
the risks and consequences of the disease to the mother and her fetus [32,42]. Nonetheless,
difficulties in diagnosis, interruption of and/or low attendance in prenatal examinations,
non-adherence or inadequate treatment regarding antibiotic dosage, and absence of
partners at prenatal appointments have been reported as risk factors for the development
and non-interruption of syphilis [42–47].”
Before: “Regarding the sociodemographic profile of pregnant women observed herein,
most cases were identified among women aged 20-39 years who self-identified as ‘mixed-race’,
had up to eight years of formal education and were mainly diagnosed with primary syphilis.
However, it worth noting that many records contained missing self-reported skin color
classification data in P1, which can be considered as a bias in the interpretation
of our results. Indeed, the data presented herein corroborate other studies that identified
a significant correlation between these sociodemographic characteristics and SiP [26,29–32,34,36,42-51].
STI and SiP were found to be more strongly associated with women who dropped out of
school, self-identified as 'black' or 'mixed-race', age below 20 years or between
20 and 30 years old [46], without access to quality health services, preventive and
educational programs or received assistance at public health care units, including
adequate prenatal care [32,43,44]. We suggest that distinct strategies are required
to reach more vulnerable populations and to minimize inequalities that enable greater
access to health services. Poverty prompts specific vulnerabilities, whether behavioral
or brought on by deficiencies in health services, such as prenatal care access and
quality, which are also significantly associated with SiP. Brazilian social inequality
in health supports the hypothesis that the prevalence of SiP is associated with a
lower socioeconomic status [32,43,44].”
After (line 384-394): “Regarding the sociodemographic profile of pregnant women observed
herein, most cases were identified among women aged 20-39 years who self-identified
as ‘mixed-race’, had up to eight years of formal education and were mainly diagnosed
with primary syphilis. However, it worth noting that many records contained missing
self-reported skin color classification data in P1, which can be considered as a bias
in the interpretation of our results. Indeed, the data presented herein corroborate
other studies [25,31–34,36,37,43–46,48–53] that identified a significant correlation
between SiP and women who dropped out of school, self-identified as 'black' or 'mixed-race',
age below 20 years or between 20 and 30 years old [48], without access to quality
health services, preventive and educational programs or received assistance at public
health care units, including adequate prenatal care [34,44,45,54,55].”
Before: “[…] The observed variations in incidence among the municipalities may be
the result of a decline in the underreporting of cases or reflect problems in local
health systems, such as a lack of access to specialized services. Importantly, incomplete
reporting hinders the elaboration of preventive strategies by policymakers, resulting
in ineffective epidemiological surveillance [51,52]. It is evident that the Brazilian
healthcare system will continue to be challenged by this scenario, as despite government
investment in awareness campaigns, the circumstances remain far from ideal. Low adherence
to treatment among patients and their partners is a main obstacle that must be overcome.
Insufficient social awareness regarding prevention and treatment reflects the urgent
need for educational policies aimed at preventing congenital infections [32,51] in
Brazil, especially in the affected macroregions and microregions identified in this
study.”
After (line 415-422): “The observed variations in incidence among the municipalities
may be the result of a decline in the underreporting of cases or reflect problems
in local health systems, such as a lack of access to specialized services. Importantly,
incomplete reporting hinders the elaboration of preventive strategies by policymakers,
resulting in ineffective epidemiological surveillance [53,63]. It is evident that
the Brazilian healthcare system will continue to be challenged by this scenario, as
despite government investment in awareness campaigns, the circumstances remain far
from ideal.”
Before: “Low adherence to treatment among patients and their partners is a main obstacle
that must be overcome. Insufficient social awareness regarding prevention and treatment
reflects the urgent need for educational policies aimed at preventing congenital infections
[32,51] in Brazil, especially in the affected macroregions and microregions identified
in this study […]
We conclude that despite the existence of control and awareness programs for STIs
[…]”
After (line 423-432): “We suggest that distinct strategies are required to reach more
vulnerable populations and to minimize inequalities that enable greater access to
health services. Poverty prompts specific vulnerabilities, whether behavioral or brought
on by deficiencies in health services, such as prenatal care access and quality, which
are also significantly associated with SiP. Brazilian social inequality in health
supports the hypothesis that the prevalence of SiP is associated with a lower socioeconomic
status [34,44,45]. SiP control programs should place greater focus on these more vulnerable
populations [44,45], especially considering that the lack of or inadequacies in public
sexual education policies for younger individuals was associated with decreased condoms
use in casual sexual relations in recent years [34] […]
(Line 442): In this way, concluded despite the existence of control and awareness
programs for […]”
Question 14. Line 315 would reference global estimates of CS by Korenromp et al stated
comment number 4.
Reply: We have changed the reference according to the reviewer's suggestion.
Question 15. Line 320 needs a reference for global BPG shortages. Suggest this reference
which highlights Brazil. Nurse-Findlay S, et al Françoise Bigirimana F, Ouedraogo
L, Pyne-Mercier L. Supply, Demand, and Shortages of Benzathine Penicillin for Treatment
of Syphilis: A Market Assessment. PLoS Medicine. 2017;14 (12):e1002473.
Reply: We have included the reference according to the reviewer's suggestion.
Question 16. Line 345 would consider the Brazilian reference Rocha AFB et al. Complications,
clinical manifestations of congenital syphilis and aspects related to its prevention:
an integrative review. https://pubmed.ncbi.nlm.nih.gov/34287560/.
Reply: We have changed the reference according to the reviewer's suggestion.
Question 14. Discussion lines 326 -321 from “A similar prevalence… “Would delete this
phrase as it is well known that the syphilis does not preferentially affect the gender
of the infant.
Reply: We thank the reviewer for his/her criticism and politely ask him/her to reconsider
this opinion. The results presented and the discussion confirm even more the observations
made and therefore we believe that it is important to highlight them in the study,
since these data are provided by the Ministry of Health and were included in the analysis
along with the other variables.
Question 18. Recommend other areas to shorten for example: “With respect to self-reported
skin color, the majority of reported CS cases occurred among newborns identified by
the family as ‘mixed-race’. Other data have also shown that the incidence of congenital
syphilis tends to be significantly higher in black or ‘mixed-race’ children. In fact,
several studies have linked cases of CS with family history, including the racial
classification of children’s parents, with high numbers of pregnant women self-identifying
as ‘mixed-race’ or black [22–25].”……….Can be shortened to: “The majority of reported
CS cases occurred among newborns identified by the family as ‘mixed-race’ similar
to other reports [22-25]”. Shortening the discussion to the relevant details will
ensure more people read it.
Reply: We thank the reviewer for this valuable contribution. We have changed the sentence
according to the reviewer's suggestion.
Before: “With respect to self-reported skin color, the majority of reported CS cases
occurred among newborns identified by the family as ‘mixed-race’. Other data have
also shown that the incidence of congenital syphilis tends to be significantly higher
in black or ‘mixed-race’ children. In fact, several studies have linked cases of CS
with family history, including the racial classification of children’s parents, with
high numbers of pregnant women self-identifying as ‘mixed-race’ or black [22–25].”
After: (line 355-355): The majority of reported CS cases occurred among newborns identified
by the family as ‘mixed-race’ similar to other reports [31–34].
Question 19. Citation 32 would change to the global guidelines https://www.who.int/reproductivehealth/publications/rtis/syphilis-ANC-screenandtreat-guidelines/en/.
Reply: The reference has been updated as suggested.
Before: 32. Newman L, Kamb M, Hawkes S, Gomez G, Say L, Seuc A, et al. Global estimates
of syphilis in pregnancy and associated adverse outcomes: analysis of multinational
antenatal surveillance data. PLoS Med. 2013;10: e1001396. doi:10.1371/journal.pmed.1001396”.
Reference # 39 (line 570-573): World Health Organization. WHO guideline on syphilis
screening and treatment for pregnant women. World Health Organization, 2017.
Question 20. The paragraphs starting on lines 380 and 394 are nearly identical in
content and interpretation. Would delete one of these paragraphs. There are multiple
examples of this type of duplication in the discussion. As much as possible, would
recommend that the authors stay close to the findings reflected from their spatiotemporal
analysis with aa greatly shortened summary of the literature that contributes to the
understanding of risk factors and other contributors to increasing syphilis diagnoses
in Brazil.
Reply: We appreciate the suggestion. We deleted what was repeated and joined the information
in a single paragraph.
Before: “Regarding the sociodemographic profile of pregnant women observed herein,
most cases were identified among women aged 20-39 years who self-identified as ‘mixed-race’,
had up to eight years of formal education and were mainly diagnosed with primary syphilis…”
“Several child and maternal factors have been associated with increased risk and vulnerability
to CS, such as self-reported skin color, socioeconomic status and maternal age [24].
In fact, STI and SiP were found to be more strongly associated with women who dropped
out of school, self-identified as 'black' or 'mixed-race', were under 20 years of
age or between 20 and 30 years old [41], had limited access to quality health services,
preventive and educational programs or received assistance at public health care units,
but without adequate prenatal care [25,35,36].”
After (line 384-394): “Regarding the sociodemographic profile of pregnant women observed
herein, most cases were identified among women aged 20-39 years who self-identified
as ‘mixed-race’, had up to eight years of formal education and were mainly diagnosed
with primary syphilis. However, it worth noting that many records contained missing
self-reported skin color classification data in P1, which can be considered as a bias
in the interpretation of our results. Indeed, the data presented herein corroborate
other studies [25,31–34,36,37,43–46,48–53] that identified a significant correlation
between SiP and women who dropped out of school, self-identified as 'black' or 'mixed-race',
age below 20 years or between 20 and 30 years old [48], without access to quality
health services, preventive and educational programs or received assistance at public
health care units, including adequate prenatal care [34,44,45,54,55].”
Author's Reply to the Review Report (Reviewer 3)
The manuscript PONE-D-21-31051, entitled "Spatiotemporal distribution analysis of
syphilis in Brazil: Cases of congenital and syphilis in pregnant women from 2001-2017"
is an interesting paper and highlights an important problem for public health in Brazil.
I have few comments and suggestions:
Question 1. Pag. 3, lines 56-58: Brazilian data in the first paragraph should be updated.
The last data are from 2020.
Reply: Thank you for the suggestion to update the information. We have made the suggested
correction by changing the reference.
Before: “Increasing incidence and prevalence has been reported since 2008 in adults
between 15 and 49 years of age, being 10.6 million cases of syphilis”.
After (line 54-57): “According to the number of reported cases of curable STIs in
2016, only 6.3 million (1.67%) were syphilis in women and men aged 15-49 years. Looking
at the period from 2012 to 2016, the estimated global prevalence was 0.5% and the
incidence was estimated at 1.7 cases per 1,000 women and 1.6 cases per 1,000 men [2]’’.
Question 2. Pag.3, lines 69-70: Even if the paper is about syphilis in pregnancy and
congenital syphilis, it should be included that there is an ordinance for syphilis
in adults (acquired syphilis). It is an infection of compulsory notification since
2010.
Reply. We welcome the suggestion and agree that acquired syphilis should be included.
However, we have had some difficulty obtaining and analyzing these data. Despite the
reporting requirement, we were unable to obtain the raw data from SINAN, and the available
information is already published in the Epidemiologic Bulletins of the Ministry of
Health, in a shorter time period than that examined in this paper. Furthermore, when
using this information from the epidemiological bulletins for joinpoint regression
analyzes using APC (Annual Percent Change), acquired syphilis did not show distinct
periods such as CS and SiP. This result does not confirm the increase in the number
of cases in Brazil and could be due to the lack of information in the period proposed
by the study.
Question 3. Pag. 5, line 115: Change “Brazilian National Census” to Brazilian National
Estimates”. The last census was in 2010.
Reply. We have replaced “Brazilian National Census” with Brazilian National Estimates:
Before: “According to the 2015 Brazilian national census, the country’s total […]’’
After (line 123): According to the 2015 Brazilian national estimates, the country’s
total […]’’
Question 4. Page 9, lines 220-221: 40% of the clinical stage of syphilis were classified
as primary. The misclassification is a big problem in Brazil and the authors should
emphasize it in the discussion section.
Reply: Good observation. We appreciate and accept the suggestion.
Before: No text.
After (line 394-398): “As for cases of primary syphilis in pregnant women, it is noteworthy
that like the misclassification of latent syphilis in the United States [56], the
estimated number of 40% found here may also have been misclassified, as this is considered
a major problem. in Brazil. In fact, the correct classification of the clinical stage
of the infection depends on experienced medical personnel’’.
Question 5. Page 11, lines 252-256: The authors describe data of syphilis in pregnancy
during pregnancy. In page 13, lines 300-308, the authors need to highlight in the
discussion that the compulsory notification started in 2005 for pregnant women.
Reply. Thanks for the observation.
Before: “Additionally, the detection rate in pregnant women rose from 0.5 to 17.2
cases per 1,000 live births between 2005 and 2017’’.
After (line 324-327): …which indicate an increase from 1.7 to 8.6 cases/1,000 live
births for CS between 2003 and 2017 and 0.5 to 17.2 cases per 1,000 live births for
SiP between 2005 and 2017, with SiP only becoming reportable in 2005.
Question 6. Page 15, lines 350-355: Are there links to access these documents listed
in Portuguese? If not, they could be excluded.
Reply. Access links have been added in the references. Thanks for the suggestion.
Before: “[…] provided to all pregnant women (Brasil. Ministério da Saúde. Secretaria
de Atenção à Saúde. Departamento de Ações Programáticas Estratégicas. Área Técnica
de Saúde da Mulher 2006). It is known that the incidence of syphilis is considered
to be an important indicator of accessibility and prenatal care quality (Ministério
da Saúde. Secretaria de Vigilância em Saúde. Programa Nacional de DST/AIDS 2007, Ministério
da Saúde. Portaria nº 1.459, de 24 de junho de 2011).”
After (line 366-367): “properly provided to all pregnant women [35]. It is known that
the incidence of syphilis is an important indicator of accessibility and prenatal
care quality [28].”
Reference # 28 (line 533-537): Ministério da Saúde. Secretaria de Atenção à Saúde.
Departamento de Ações Programáticas Estratégicas. Área Técnica de Saúde da Mulher.
2006 [Cited 2022 March 25]. Available: https://bvsms.saude.gov.br/bvs/publicacoes/relatorio_2003a2006_politica_saude_mulher.pdf.
Reference # 35 (line 558-560): Ministério da Saúde. Secretaria de Vigilância em Saúde.
Programa Nacional de DST/AIDS 2007. Portaria nº 1.459, de 24 de junho de 2011. Available:
https://bvsms.saude.gov.br/bvs/saudelegis/gm/2011/prt1459_24_06_2011.html
Question 7. Page 15, lines 365-368: Authors explain about syphilis tests during pregnancy.
It is important to include the recommendation to test for syphilis during labor. Both
WHO and Brazilian guidelines recommend it.
Reply Thank you for pointing out this important information.
Before: “It is therefore important that all pregnant women be tested at the first
prenatal visit scheduled in the first trimester of pregnancy, with repeat testing
performed at around 28 weeks (beginning of the third trimester) in order to promptly
implement appropriate therapy if necessary”.
After (line 374-377): Therefore, it is important that all pregnant women be tested
at the first prenatal visit scheduled (1st trimester), with 28 weeks pregnant and
at the time of delivery to promptly implement appropriate therapy if necessary [32,38–42].
Question 8. The discussion section is a little to long, it should be optimized. There
is discussion on demographics, as age, mixed-race, education, in three different parts.
Reply: We appreciate the suggestion. Possible changes have been made to improve readability.
Before: “Herein, most cases of CS were diagnosed less than seven days after birth,
and 70% of mothers reported receiving prenatal care. Most cases of CS are asymptomatic
at birth, however, the high coverage of hospital births with a notification system
for CS based on maternity services are the main reason why diagnosis usually occurs
within seven days after birth (typically between the 1st and 2nd day of life) [31,32].
Contrarily, in addition to prematurity, newborns can present signs and symptoms of
infection soon after birth, including low birth weight, anemia, jaundice, respiratory
distress, visceromegaly, congenital malformations, serosanguinous discharge and rhinitis,
skin lesions, heart disease and/or hearing loss [33]. Interestingly, it was found
that despite the predominance of prenatal care in 70+% of the CS cases investigated
herein, significantly high numbers of cases of CS were nonetheless reported throughout
the country […].”
After (line 357-363): “Herein, most cases of CS were diagnosed in asymptomatic children
less than seven days after birth with 70% mothers reported receiving prenatal care.
However, the high coverage of hospital births with a notification system for CS based
on maternity services are the main reason why diagnosis usually occurs within seven
days after birth (typically between the 1st and 2nd day of life) [33,34]. Interestingly,
it was found that despite the predominance of prenatal care in 70+% of the CS cases
investigated herein, significantly high numbers of cases of CS were nonetheless reported
throughout the country.”
Before: “However, despite the expansion of diagnosis and treatment in Brazil, increases
in the number of cases indicates shortcomings in the efforts designed to control and
prevent this STI [34]. At the same time, health authorities have also attributed increases
in incidence to the success of public health actions in improving detection rates.
Nevertheless, actions designed to improve health care access for pregnant women have
performed poorly in terms of CS prevention [26]. One of the main purposes of prenatal
care is to assist women in a qualified and humanized way beginning in the early stages
of pregnancy, adopting early screening procedures coupled with timely interventions
[35]. Early diagnosis and treatment of SiP, ideally before the 20th week of pregnancy,
can reduce CS-related cases, such as miscarriages, stillbirths, and infant deaths
[36]. It is therefore important that all pregnant women be tested at the first prenatal
visit scheduled in the first trimester of pregnancy, with repeat testing performed
at around 28 weeks (beginning of the third trimester) and on admission to childbirth
in order to promptly implement appropriate therapy if necessary [37-40]. Information
regarding CS vertical transmission should be provided to pregnant women at the onset
of prenatal care, and physicians must inform patients regarding the risks and consequences
of the disease to the mother and her fetus [30,41].
An established diagnosis does not guarantee adhesion to appropriate treatment by the
patient. The late onset of symptoms (mostly detected in the third trimester), the
interruption of and/or low attendance in prenatal examinations, difficulties in diagnosis,
a lack of information regarding infection and unsafe sexual practices have been reported
as risk factors for the development of syphilis [42–44]. Furthermore, errors in antibiotic
dosage have also been of concern. Other key factors, such as conjugal infidelity,
the absence of partners at prenatal appointments and reluctance in adhering to treatment
protocols have also been reported by patients [41,45].”
After (line 368-383): “Despite the expansion of diagnosis and treatment in Brazil,
increases in the number of cases indicates shortcomings in the efforts designed to
control and prevent this STI [36]. At the same time, health authorities have also
attributed increases in incidence to the success of public health actions in improving
detection rates. Nevertheless, actions designed to improve health care access for
pregnant women have performed poorly in terms of CS prevention [25]. Early diagnosis
and treatment of SiP can reduce CS-related cases, such as miscarriages, stillbirths,
and infant deaths [37]. Therefore, it is important that all pregnant women be tested
at the first prenatal visit scheduled (1st trimester), with 28 weeks pregnant and
at the time of delivery in order to promptly implement appropriate therapy if necessary
[32,38–42]. Information regarding CS vertical transmission should be provided to pregnant
women at the onset of prenatal care, and physicians must inform patients regarding
the risks and consequences of the disease to the mother and her fetus [32,42]. Nonetheless,
difficulties in diagnosis, interruption of and/or low attendance in prenatal examinations,
non-adherence or inadequate treatment regarding antibiotic dosage, and absence of
partners at prenatal appointments have been reported as risk factors for the development
and non-interruption of syphilis [42–47].”
Before: “Regarding the sociodemographic profile of pregnant women observed herein,
most cases were identified among women aged 20-39 years who self-identified as ‘mixed-race’,
had up to eight years of formal education and were mainly diagnosed with primary syphilis.
However, it worth noting that many records contained missing self-reported skin color
classification data in P1, which can be considered as a bias in the interpretation
of our results. Indeed, the data presented herein corroborate other studies that identified
a significant correlation between these sociodemographic characteristics and SiP [26,29–32,34,36,42-51].
STI and SiP were found to be more strongly associated with women who dropped out of
school, self-identified as 'black' or 'mixed-race', age below 20 years or between
20 and 30 years old [46], without access to quality health services, preventive and
educational programs or received assistance at public health care units, including
adequate prenatal care [32,43,44]. We suggest that distinct strategies are required
to reach more vulnerable populations and to minimize inequalities that enable greater
access to health services. Poverty prompts specific vulnerabilities, whether behavioral
or brought on by deficiencies in health services, such as prenatal care access and
quality, which are also significantly associated with SiP. Brazilian social inequality
in health supports the hypothesis that the prevalence of SiP is associated with a
lower socioeconomic status [32,43,44].”
After (line 384-394): Regarding the sociodemographic profile of pregnant women observed
herein, most cases were identified among women aged 20-39 years who self-identified
as ‘mixed-race’, had up to eight years of formal education and were mainly diagnosed
with primary syphilis. However, it worth noting that many records contained missing
self-reported skin color classification data in P1, which can be considered as a bias
in the interpretation of our results. Indeed, the data presented herein corroborate
other studies [25,31–34,36,37,43–46,48–53] that identified a significant correlation
between SiP and women who dropped out of school, self-identified as 'black' or 'mixed-race',
age below 20 years or between 20 and 30 years old [48], without access to quality
health services, preventive and educational programs or received assistance at public
health care units, including adequate prenatal care [34,44,45,54,55].
Before: “[…] The observed variations in incidence among the municipalities may be
the result of a decline in the underreporting of cases or reflect problems in local
health systems, such as a lack of access to specialized services. Importantly, incomplete
reporting hinders the elaboration of preventive strategies by policymakers, resulting
in ineffective epidemiological surveillance [51,52]. It is evident that the Brazilian
healthcare system will continue to be challenged by this scenario, as despite government
investment in awareness campaigns, the circumstances remain far from ideal. Low adherence
to treatment among patients and their partners is a main obstacle that must be overcome.
Insufficient social awareness regarding prevention and treatment reflects the urgent
need for educational policies aimed at preventing congenital infections [32,51] in
Brazil, especially in the affected macroregions and microregions identified in this
study.”
After (line 415-422): “The observed variations in incidence among the municipalities
may be the result of a decline in the underreporting of cases or reflect problems
in local health systems, such as a lack of access to specialized services. Importantly,
incomplete reporting hinders the elaboration of preventive strategies by policymakers,
resulting in ineffective epidemiological surveillance [53,62]. It is evident that
the Brazilian healthcare system will continue to be challenged by this scenario, as
despite government investment in awareness campaigns, the circumstances remain far
from ideal.”
Before: “Low adherence to treatment among patients and their partners is a main obstacle
that must be overcome. Insufficient social awareness regarding prevention and treatment
reflects the urgent need for educational policies aimed at preventing congenital infections
[32,51] in Brazil , especially in the affected macroregions and microregions identified
in this study […]
We conclude that despite the existence of control and awareness programs for STIs
[…]”
After (line 423-432): We suggest that distinct strategies are required to reach more
vulnerable populations and to minimize inequalities that enable greater access to
health services. Poverty prompts specific vulnerabilities, whether behavioral or brought
on by deficiencies in health services, such as prenatal care access and quality, which
are also significantly associated with SiP. Brazilian social inequality in health
supports the hypothesis that the prevalence of SiP is associated with a lower socioeconomic
status [34,44,45]. SiP control programs should place greater focus on these more vulnerable
populations [44,45], especially considering that the lack of or inadequacies in public
sexual education policies for younger individuals was associated with decreased condoms
use in casual sexual relations in recent years [34].
(Line 441): In this way, concluded despite the existence of control and awareness
programs for […]
Question 9. I did not see in the discussion section a discussion about the use of
secondary data. It is important to report it.
Reply: We thank the reviewer for the suggestion.
Before: “We performed a systematic spatiotemporal analysis of reported cases of CS
and SiP in Brazil…’’
After (line 314-315): We performed a systematic spatiotemporal analysis using secondary
data of reported cases of CS and SiP in Brazil…
Question 10. References should be revisited because they should follow the journal
recommendations. There are different presentation of the number of authors and one
of them are in caps letter.
Reply: We thank the reviewer for calling this to our attention. Changes have been
made.
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